What are the diagnostic criteria and treatment options for Evan syndrome?

Diagnosis of Evans Syndrome

Evans syndrome is diagnosed by demonstrating the simultaneous or sequential occurrence of immune thrombocytopenia (platelet count <100,000/μL) and autoimmune hemolytic anemia with a positive direct antiglobulin test (DAT), after excluding other known underlying etiologies. 1, 2

Diagnostic Criteria

The diagnosis requires two essential components:

• Immune thrombocytopenia: Platelet count typically <100,000/μL with evidence of immune-mediated platelet destruction 1
• Autoimmune hemolytic anemia: Hemolytic anemia with elevated reticulocyte count, elevated indirect bilirubin, decreased haptoglobin, and positive DAT (direct antiglobulin test) 1, 2

The cytopenias may occur simultaneously or sequentially, and the diagnosis is one of exclusion—other causes must be ruled out 2, 3.

Required Diagnostic Workup

Initial Laboratory Evaluation

Complete blood count with differential, peripheral blood smear, and reticulocyte count are mandatory first steps. 1, 2

• Peripheral blood smear: Look for spherocytes, polychromasia, and reduced platelets 1
• Direct antiglobulin test (DAT): Must be positive to confirm the autoimmune hemolytic component 4, 1
• Hemolysis markers: Elevated indirect bilirubin, decreased haptoglobin, elevated LDH 1
• Reticulocyte count: Should be elevated (unless bone marrow suppression present) 4, 1

Bone Marrow Examination

Bone marrow evaluation is strongly recommended in the diagnostic workup of Evans syndrome. 1, 2

This is critical to:

• Evaluate for underlying lymphoproliferative disorders 4, 1
• Exclude myelodysplastic syndromes or aplastic anemia 1
• Demonstrate adequate megakaryocytes and erythroid hyperplasia 1

The 2024 expert consensus panel specifically recommended bone marrow evaluation and CT scan as part of extensive diagnostic testing 2.

Exclusion of Secondary Causes

Testing for underlying conditions is essential before confirming primary Evans syndrome. 4, 2

Screen for:

• Infections: HIV, hepatitis C virus, hepatitis B virus, CMV, and Helicobacter pylori 4
• Lymphoproliferative disorders: CT scan and bone marrow examination 2
• Autoimmune conditions: Systemic lupus erythematosus and antiphospholipid syndrome 4
• Immunodeficiency syndromes: Including common variable immune deficiency 5

Treatment Approach

First-Line Treatment

Prednisone 1-2 mg/kg/day orally is the recommended first-line treatment, with the goal of increasing platelet count to 30-50 × 10⁹/L within 2-4 weeks. 1, 2

• Continue for 2-4 weeks, then taper over 4-6 weeks to the lowest effective dose 4
• Different tapering schedules apply: The 2024 consensus recommended different treatment durations and tapering for immune thrombocytopenia versus autoimmune hemolytic anemia components 2

Intravenous immunoglobulin (IVIG) 1 g/kg should be added when rapid platelet increase is required, particularly with severe bleeding or platelet count <25,000/μL 4, 1, 2.

Second-Line Treatment

Rituximab is strongly recommended as second-line treatment in specific scenarios: 1, 2

• Cold-type AIHA (actually recommended as first-line in this subtype) 1, 2
• Warm-type AIHA with antiphospholipid antibodies or previous thrombotic events 1
• Associated lymphoproliferative diseases 2
• Chronic ITP component 1

However, rituximab is discouraged for patients with immunodeficiency or severe infections, with the same applying to splenectomy 2.

Thrombopoietin receptor agonists (eltrombopag, romiplostim) are recommended for chronic ITP component, with response rates of 70-81% for eltrombopag and 79-88% for romiplostim 4, 1, 6. These are particularly recommended in cases with previous grade 4 infection 2.

Refractory Disease

For refractory cases, the treatment hierarchy is:

• Third-line options: Fostamatinib (recommended as third-line or further-line, suggested as second-line for patients with previous thrombotic events), immunosuppressive agents (cyclophosphamide, mycophenolate mofetil, ciclosporin) 6, 2, 7
• Severe refractory cases: Plasma exchange, alemtuzumab (requires prolonged antimicrobial prophylaxis due to severe immunosuppression) 6
• Last resort: Hematopoietic stem cell transplantation for cases unresponsive to all immunosuppressive agents 6, 7

Common Pitfalls

• Failing to perform bone marrow examination: This is strongly recommended but often omitted, potentially missing underlying lymphoproliferative disorders 1, 2
• Misdiagnosing DIC as Evans syndrome: The presence of disseminated intravascular coagulation can make diagnosis challenging and requires strong clinical suspicion 8
• Using rituximab in immunodeficient patients: This significantly increases infection risk and should be avoided 2
• Inadequate screening for secondary causes: Evans syndrome is a diagnosis of exclusion; failure to exclude infections, lymphoproliferative disorders, and autoimmune conditions can lead to inappropriate management 4, 2, 3